Preclinical studies suggest that in addition to the well-known direct damage to the myocardium, anthracycline antineoplastic drugs exert toxic effects on the cardiovascular autonomic system as well. To investigate whether this phenomenon occurs in the clinic, we carried out noninvasive, widely used tests of cardiovascular autonomic physiology in 55 women with stage II or III breast cancer. In all, 31 were being treated with anthracycline-containing chemotherapy regimens, and 24 who were receiving CMF (cyclophosphamide, Methotrexate, and fluorouracil) served as controls. Of 279 tests conducted in anthracycline (A)-treated patients, 123 were abnormal, vs 54 of 216 tests carried out in 24 controls (44% vs 25%; P less than 0.005). Abnormal variations in heart rate on standing and in diastolic blood pressure during handgrip was found in 25 (81%) and 17 patients receiving A, vs 9 (37%; P less than 0.005) and 5 (21%; P less than 0.0001), respectively, in controls. The incidence of abnormal tests was significantly higher in A-treated patients greater than 60 years of age (41%) vs 67%; P less than 0.05). Radionuclide ventriculography was carried out in 19 patients who showed abnormal tests of cardiovascular autonomic function after greater than or equal to 6 courses of a-containing chemotherapy; only 1 of them had abnormal cardiac contractility (global hypokinesia), suggesting that abnormal tests of cardiovascular autonomic function may occur in the absence of a detectable deterioration in left ventricular ejection fraction. A large number of factors may alter cardiovascular autonomic function in cancer patients, including age, radiation therapy to the chest, and multidrug treatment. Even after correcting for the most obvious of these, chemotherapy with anthracyclines is associated with a significantly higher percentage of abnormal tests for cardiovascular autonomic function. Although indirect and semi-quantitative, our results are compatible with the idea of A-induced cardiac autonomic dysfunction.